Although psychological stress (PS) is well recognized to provoke and exacerbate cutaneous disorders the mechanism(s) for this are unknown. Recently, we have shown that permeability barrier homeostasis is impaired in animal models of PS and in humans with PS. PS increases serum glucocorticoid (GC) levels and inhibition of GC action prevents the barrier abnormality. Moreover, GC treatment similarly produces an abnormality in barrier function due to the decreased production and secretion of lamellar bodies (LB), which can be explained by GC inhibiting the epidermal synthesis of cholesterol, fatty acids, and ceramides. Topical lipids correct the barrier abnormality directly demonstrating that the inhibition of epidermal lipid synthesis is a major factor accounting for the abnormal barrier. GC treatment also compromises SC integrity and cohesion due to a decrease corneodesmosomes (CD) density. Topical lipids improve the defect in SC integrity and cohesion indicating that a deficiency of lipids also plays a role in mediating these abnormalities. Hypothesis: PS inhibits barrier homeostasis by stimulating GC production, which inhibits epidermal lipid synthesis resulting in a decrease in LB formation/secretion leading to impaired barrier homeostasis. Additionally, the PS/GC induced decrease in lamellar membranes in the SC increases protease activity reducing CD density, thereby decreasing SC integrity and cohesion. Correction of the lipid deficiency ameliorates the harmful consequences of PS and GC treatment on the epidermis. Aim 1- To determine if PS, by increasing GC production, a) impairs barrier homeostasis by decreasing epidermal lipid synthesis and LB formation/ secretion and b) compromises SC integrity and cohesion by decreasing CD density in the SC. Aim 2- To determine the biochemical basis and molecular mechanisms responsible for the PS/GC induced inhibition of epidermal lipid synthesis. Aim 3-To determine the mechanisms for the abnormality in SC integrity and cohesion, we will assess the effects of PS/GC on both the formation and degradation of CD. Aim 4: To determine if the abnormalities in permeability barrier homeostasis and SC integrity/ cohesion induced by GC treatment in humans, are due to the inhibition of epidermal lipid synthesis.